The liver is a central organ for coordinating much of metabolism and has a large capacity for fatty acid uptake. Considerable evidence has accumulated to show that in addition to a diffusional component, the intestine, heart, adipose tissue, and the liver express a saturable and specific long-chain fatty acid transport system. Identifying the postulated liver fatty acid transporter is of considerable importance, since both increased and decreased hepatic LCFA uptake have been implicated in diseases such as type-2 diabetes and acute liver failure. Investigators have found several membrane proteins that increase the uptake of LCFAs when overexpressed in cultured mammalian cells. The most prominent and best characterized of these are FAT/CD36 and fatty acid transport proteins (FATPs, solute carrier family 27). However, neither the better studied FATPs, FATP1 and -4, nor CD36 are expressed at appreciable levels in the liver. Therefore, we have identified FATPs that are expressed in the liver and have characterized their contribution to protein-mediated LCFA uptake and general energy homeostasis. We have identified two FATP family members, FATP5 and -2, as possible candidates for this role. FATP2 is expressed in liver and kidney, while FATP5 expression is liver-specific. The purpose of this proposal is to determine the contribution of FATP5 to hepatic fatty acid uptake. To accomplish this, we will determine the localization and regulation of FATP5 in the liver and generate animal models for loss and gain of FATP5 function. To this end, we have generated FATP5 null mice, which show reduced hepatic fatty acid uptake and diminished liver triglyceride content. We will use this unique model system to explore the role of liver LCFA uptake for energy homeostasis and the etiology of diseases, particularly of type-2 diabetes. Excessive liver TG accumulation is a well-described feature of the """"""""metabolic syndrome"""""""" and may, in part, be responsible for insulin resistance and increased glucose levels. To evaluate FATP5 as a potential target for therapeutic intervention, we will test whether FAT5 null animals show reduced lipid accumulation, and increased insulin sensitivity in dietary and genetically induced models of diabetes. We will also test the hypothesis that the converse is true, by generating FATP5 transgenic mice, which may have increased liver LCFA uptake. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Serrano, Jose
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University of California Berkeley
Schools of Earth Sciences/Natur
United States
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